TLyP-1 Modified And Oxygen Generated Nanotheranostics For The Enhanced Photodynamic Therapy

Photodynamic therapy?PDT?is a process in which photosensitizers produce reactive oxygen species?ROS?with oxygen to kill tumor cells under the excitation of light.PDT has attracted much attention due to its minimal invasiveness and efficiency.However,most tumors have important characteristics of severe hypoxia and dense tissue,which not only hinder the deep penetration of photosensitizers,but also significantly inhibit the production of ROS.Therefore,new strategies are urgently needed to reduce tumor hypoxia and enhance the drug penetration to improve the effect of PDT.Manganese dioxide can react with hydrogen ions and hydrogen peroxide in the tumor microenvironment to generate oxygen to alleviate the problem of tumor hypoxia,and meanwhile the generated divalent manganese ions during the process can be used for T₁magnetic resonance imaging contrast agent.Tumor homing&penetrating polypeptide owns the homing ability into tumor tissues or blood vessels.It can recognize and bind the specific receptors or markers on the surface of tumor tissues or blood vessels,so it can penetrate and reach into the deepeth of tumor.Therefore,developing a kind of nano-drug with the capacity of tumor penetratioin and homing,oxygen production and imaging can alleviate the problem of hypoxia and poor penetration of malignant tumors,making cancer treatment more accurate and efficient.Based on the above background,this thesis aimd to construct a new type of nanotheranostic system which was modified with tumor penetrating and homing peptides and could generate oxygen for magnetic resonance imaging guided high efficient PDT.Firstly,nanographene oxide?GO?was functionlized with poly?acrylamine hydrochloride?and reacted with potassium permanganate for growing manganese dioxide nanoparticles on GO in situ.Then,the tumor homing&penetrating peptide tLyP-1 was modified to yield the nanocarrier GM@tLyP-1.Finally,Ce6 was absorbed by?-?stacking and hydrophobic interaction to obtain the final nanocomposite GM@tLyP-1/Ce6,and the drug loading rate was about 45%.The electron microscope images showed that GM@tLyP-1/Ce6 was uniformly distributed in a sheet shape,with the lateral dimensions of about 150 nm,and had considerable efficiency of oxygen generation and ROS yield.GM@tLyP-1/Ce6 could penetrate deeply into the tumor with a penetration depth of about90?m into the tumor sphere model of mouse breast cancer 4T1 cells.Under the irradiation of 660 nm laser,this nanocomposite has an obviously enhanced PDT effect with the cell survival rate reduced to 18%,and the oxygen production enhanced the PDT efficacy by nearly two times.Finally,the in vivo experiments showed that GM@tLyP-1/Ce6 had a good magnetic resonance imaging effect,and the hypoxia problem at the tumor site of4T1 mouse breast cancer model was significantly alleviated.Thus the tumor growth was significantly inhibited.And the biochemical analysis of major organ tissue sections,blood routine,liver function,and kidney function demonstrated the low toxic and side effects.The study of this thesis shows that GM@tLyP-1/Ce6 has excellent tumor penetration and homing ability,significantly enhances the PDT effect by oxygen production and meanwile improves the magnetic resonance imaging effect,which is very promising in the field of tumor diagonistis and therapy.